The binding and activation characteristics of biological receptors will be studied in membranes from brain and in peripheral organs. Membrane fractions from brain that exhibit high affinity binding of 5-hydroxytryptamine (5-HT) and D-lysergic acid diethylamide (LSD) will be characterized by enrichment and isolation procedures. The interaction of other serotonergic and psychotropic drugs with these receptors will be studied, as well as the interaction of D-LSD with the dopaminergic system to seek a relation of binding measurements to pharmacological effects of the drugs. Additional characteristics of high affinity binding will be examined: regional distribution in the brain, site-directed chemicals and enzymes, and the effects of prior in-vivo treatment. The relationship between molecular structure and the biological properties of active drugs will be studied by newly developed methods of quantum mechanics, describing the electronic events related to receptor binding and activation. The methods are based on ab-initio molecular orbital calculations and drug-receptor interactions will be simulated and analyzed from the characteristics of the electrostatic interaction potentials of the drugs, their susceptibility to polarization and the changes induced in the electronic structure of the drugs by the interaction with models of receptor sites and environment. Multiple perturbation procedures will serve to analyze the effect of simultaneous interactions. The theoretical predictions will be tested by specific pharmacological and physiochemical experiments. The latter will include NMR, fluorescence and circular dichroism spectroscopies on the drugs and, if the receptor enrichment experiments are successful, also on the drug-receptor complexes. The experimentally and theoretically evaluated consequences of the interaction (e.g., proton and energy transfer, conformational perturbation) will be used for the rationalization of mechanisms by which receptor activation can occur. BIBLIOGRAPHIC REFERENCES: Weinstein, H., Chou, D., Kang, S., Johnson, C.L. and Green, J.P. - Reactivity Characteristics of Large Molecules and their Biological Activity: Indolealkylamines on the LSD/Serotonin Receptor. Int. J. Quantum Chem. 1976, QBS3.